Cancer is one of the leading causes of death globally. In 2015, an estimated 1,658,370 new cases of cancer will be diagnosed in the United States and 589,430 people will die from the disease. In the U.S. alone, 1,500 deaths per day are attributed to cancer, which is approximately 1 in every 4 deaths daily. Cancer is also among the leading causes of death worldwide. In 2012, there were 14 million new cases diagnosed and 8.2 million cancer-related deaths worldwide and the number is expected to be 13 million by 2030. Most deaths from cancer are caused by metastasis, for which there is no effective molecular imaging method to detect the tumor and its metastases, nor is there therapy to effectively eradicate the growth of localized and disseminated tumors.
This invention relates to a class of near-infrared (NIR) cyanine-containing dyes. NIR-dyes chemically conjugated with therapeutic drugs (referred to below as NIR dye-drug conjugates), result in effective uptake and retention of NIR dye-drug conjugates in cancer but not normal cells. The specificity of this class of NIR dye-drug conjugates for cancer but not normal cells is based upon the overexpression of membrane carrier proteins, organic anion transporting peptides (OATPs), in cancer, as compared with normal cells. The OATPs-mediated transporting mechanism is further enhanced by tumor hypoxia.
Evidence supporting the role of OATPs in mediating the uptake and retention of NIR dye-drug conjugates in cancer cells is as follows: 1) OATPs are expressed at a higher level in cancer cells, as compared to normal cells; 2) The expression of OATPs is further enhanced by tumor hypoxia, due to the induction of transcription of OATP genes by the enhanced hypoxia-inducing factor 1 (HIF-1α) in cancer cells; 3) The uptake and retention of NIR dye-drug conjugates in tumor cells can be abolished by bromsulphthalein (BSP), a known competitive OATP inhibitor; 4) Because the function of OATPs in cells is energy-dependent as carriers for drugs, metabolites and hormones, the uptake and retention of the NIR dye-drug conjugates by OATPs in cancer cells are also energy-dependent and occur only in live cells; 5) Genetic knockdown of certain isoform of OATPs in cancer cells prevents the uptake and retention of NIR dye-drug conjugates in cancer cells, whereas the overexpression of OATPs in cancer cells enhances the uptake and retention of NIR dye-drug conjugates in cancer cells; and 6) NIR dye-drug conjugates are known to interact with nucleic acids and proteins noncovalently, and, therefore, once the NIR dye-drug conjugates enter into cancer cells, they are trapped in the mitochrondrial and lysosomal compartments of the cancer cells.
These results establish the basis for the OATP-based uptake and retention of this class of NIR dye-drug conjugates by tumor cells.